A number of naturally-occuring peptides of twenty aminoacyl residues or less have important pharmacological properties. Recent pharmaceutical research has also led to the discovery of many synthetic or non-naturally occuring peptides in this class which are effective therapeutic agents. Noteworthy among these synthetic small peptides are compounds which act as either agonists or as antagonists of gonadotropin releasing hormone (GnRH, also known as "luteininzing hormone releasing hormone, LHRH), and peptides or pseudo-peptides of twenty residues or less which act to inhibit renin and are thus effective as agents for treating hypertension and related disease conditions of the cardiovascular system. A number of small peptides and modified peptides have also been found which act to modulate the natural peptide C5a.
While the discovery of peptide compounds having therapeutic value has moved rapidly in the last few years, the development of viable drug delivery systems for many of these compounds has often proved problematic. Most, if not all, of these compounds must be administered parenterally as, for example, by subcutaneous, intramuscular or intrapertoneal injection. Since most patients cannot self-administer parenteral drug formulations, it is frequently necessary that drugs of this type be administered in an out-patient setting leading to additional costs associated with their use. Administration of most of these compounds by an oral route, although more convenient, has not generally been available. Orally administered therapeutic agents are rapidly transported to the stomach and small intestine for absorption across gastro-intestinal mucosal membranes into the blood. The efficiency of absorption of a therapeutic agent (i.e. the ratio of the amount entering the blood to the mount administered) following oral administration of many drugs can be low because of several factors which serve to metabolize the administered chemical. Low absorption efficiency is particularly problematic with polypeptide therapeutic agents.
The gastrointestinal tract secretes a variety of agents that metabolize polypeptides. Exemplary of such catabolic agents are pepsin, trypsin, chymotrypsin, carboxypolypeptidases, aminopolypeptidases and dipeptidases. Polypeptides that escape catabolism in the stomach and small intestine are transported across the cells lining the gastrointestinal tract into the portal circulation, which carries absorbed polypeptides to the liver. Absorbed polypeptides are subject to further degradation by a myriad of hepatic metabolic events. Such hepatic degradation of absorbed materials from the blood before such materials enter the general systemic circulation is known in the pharmaceutical art as the "first pass effect".
As a result of these factors causing low absorptive efficiency of orally administered therapeutic agents, particularly polypeptides, if the choice of the route of administration is the oral route, it is necessary to administer large dosages of such polypeptides. This is costly in many cases and inefficient. Alternatively, such therapeutic agents can be administered via other routes such as intravenously, subcutaneously or intraperitoneally. These alternate routes are all invasive by nature and can involve pain and discomfort to a subject. There is, therefore, a pressing need for new, efficient, cost-effective and non-invasive methods and compositions for the administration to patients of therapeutic agents which would be otherwise degraded if administered orally.
The present invention provides novel compositions and methods for the oral administration of peptide therapeutic agents.